Cardiovascular diseases are the leading cause of death and disability in the world. The main underlying cause of cardiovascular diseases is atherosclerosis. High risk of atherosclerosis is often associated with viral infection, with HIV infection presenting an example of such association. We have recently established that HIV, through its protein Nef, interacts with ABCA1 and interferes with ABCA1-dependent cholesterol efflux. Mutations in ABCA1 are known to be associated with high risk of atherosclerosis, but for the first time a non- genetic mechanism of impairment of cholesterol efflux pathway has been described. This application focuses on molecular characterization of this mechanism and its contribution to HIV-induced atherosclerosis, however, this mechanism may represent a general phenomenon playing role in atherosclerosis associated with infection. Proposed studies will be performed by addressing the following Specific Aims. Specific Aim 1. Establish whether HIV exploits ABCA1-dependent cholesterol trafficking to divert cholesterol flow to lipid rafts (the sites of viral assembly). Specific Aim 2. To investigate the mechanisms and metabolic consequences of interaction between Nef and ABCA1. Specific Aim 3. Characterize the effects of Nef on development of atherosclerosis in vivo. The rationale for the proposed research is that knowledge acquired in this research may facilitate new approaches to treat cardiovascular complications of HIV disease by preventing Nef-mediated impairment of ABCA1. We also expect to gain knowledge about biological mechanisms regulating ABCA1 intracellular trafficking in infected and normal cells, thus extending the applications of this research to non-viral atherosclerosis. We are especially well prepared to successfully complete the proposed studies, as we were the first to characterize the effect of HIV infection on reverse cholesterol transport, and we have a long history of successful collaboratio supported by several previous NIH awards. PUBLIC HEALTH RELEVANCE: The proposed studies are highly relevant to public health as they address important problems related to clinical and basic cardiovascular research, including why HIV infection increases the risk of atherosclerosis and coronary artery disease, and may also provide clues to dislipidemia observed in HIV-infected patients. These studies are expected to establish a link between the viral infection and atherosclerosis; such link may help understand the contribution of other viral infections to pathogenesis of atherosclerosis. In addition, the proposed studies will define the mechanisms regulating physiological turnover of ABCA1 and thus may contribute to development of new therapeutic agents to treat atherosclerosis.